The present invention relates to the use of 1-phenyl-3-dimethylaminopropane compounds for the production of medicaments for treating neuropathic, preferably mononeuropathic and/or polyneuropathic pain, particularly preferably polyneuropathic pain, and also preferably diabetic neuropathic pain, preferably diabetic peripheral neuropathic pain, and furthermore preferably for treating diabetic peripheral neuropathy.
The normal physiological pain sensation, which serves as a protective function for the organism, is transmitted via nerve fibres as a response to corresponding painful stimuli. This is referred to as nociceptive pain. This nociceptive pain may be acute or chronic, somatic or visceral, and may be present with or without an inflammatory component. Appropriate stimuli may be mechanical (e.g. pressure), thermal (e.g. heat) or chemical (e.g. acid). Also, electrical stimuli may be perceived as painful.
In contrast to nociceptive pain—and also in most cases not treatable with the same means—neuropathic pain (a non-nociceptive pain; for a review see Hansson et al., 2001 Neuropathic Pain; Pathophysiology and Treatment in Progress in Pain Research and Management, Vol. 21 eds. Hansson et al. IASP Press, Seattle; Bridges et al., 2001 Br J Anaesthesia 87:12-26) is characterized by the occurrence of spontaneous pain and/or pain triggered by abnormal stimuli. Spontaneously occurring pain results for example from so-called ectopic activity of the pain-conducting nerve fibres. In this case the nerve fibre sends a pain signal from the periphery to the central nervous system even though there was no appropriate stimulus. An example of pain that is triggered by an abnormal stimulus is the phenomenon of allodynia. Allodynia is defined as a painful sensation produced by a normally non-painful stimulus. Allodynia is not restricted to neuropathic pain. Thus, allodynia occurs for example in non-neuropathic conditions such as sunburn or arthritis. The underlying mechanisms of allodynia differ however in principle from one another and can be classified by a detailed medical case history and investigation.
A further example of abnormal pain sensation is hyperalgesia. In this case a normally painful stimulus is perceived as producing a more severe pain than would be the case in a healthy situation. This type of increased pain perception occurs not only in neuropathic pain but also for example in inflammatory pain, where however it has a different cause (inflammation) than in neuropathic pain.
Various metabolic diseases may be the cause of neuropathic changes and may subsequently be implicated in neuropathic pain. An example of such a neuropathy is diabetic neuropathy, which occurs in a large number of patients suffering from diabetes mellitus and may be associated with a large number of clinical symptoms such as a feeling of numbness, tingling sensation, or pain. The most common form of diabetic neuropathy is distal symmetrical sensomotor polyneuropathy.
Neuropathic pain occurs inter alia after damage to peripheral or central nerves and can therefore be induced and observed in animal experiments by targeted lesions of individual nerves. Two possible animal models are the nerve lesion according to Bennett (Bennett and Xie, 1988 Pain 33:87-107) as well as that according to Chung (Kim and Chung, 1992 Pain 50:355-363). In the Bennett model the sciatic nerve is bound unilaterally with loose ligatures; in the Chung model two spinal nerves are bound unilaterally. In both cases the development of symptoms of neuropathic pain can be observed and quantified by means of thermal or mechanical allodynia.
A known animal model for investigating diabetic neuropathy is the induction of diabetes in rodents by administration of a single dose of streptozotocin, an antibiotic extract from Streptomyces acromogenes, which selectively damages the 6 cells of the pancreas. After some time the animals exhibit typical symptoms of diabetic neuropathic pain, such as for example mechanical, thermal or chemical hyperalgesia (Courteix et al., 1993 Pain 53:81-88).
To treat neuropathic pain, among other things, gabapentin is used, which however is relatively ineffective, and then only at significant dosages. On the other hand morphine is also often used, the range of side effects of which are, as is known, not without problems. Against the background of the prior art there was therefore a need for compounds with a favorable ratio of effectiveness to side effects, and to provide compounds for the treatment of neuropathic pain.